Novel beta-phenyl-alpha-oxysubstituted propionic derivatives: process for its preparation and their use in the preparation of pharmaceutically important compounds

ABSTRACT

The present invention relates to novel propionic acid derivatives. More particularly, the present invention relates to beta-phenyl alpha-oxysubstituted propionic acids of the general formula (I). The present invention also relates to processes for the preparation of compounds of the formula (I) and their use in the preparation of compounds of formula (II).

FIELD OF THE INVENTION

The present invention relates to novel propionic acid derivatives. Moreparticularly, the present invention relates to β-phenyl α-oxysubstitutedpropionic acids of the general formula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their salts, their solvates wherein W represents NR¹²,R¹² represents hydrogen, R¹⁰ and R¹¹ may be same or different andrepresent hydrogen or substituted or unsubstituted group selected formalkyl, alkoxy, aryl or aralkyl group; Ar represents substituted orunsubstituted divalent single or fused aromatic or heterocyclic group;R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen,lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶forms a bond together with R⁵; R⁷ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups;R⁸ may be hydrogen or substituted or unsubstituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents oxygen, sulfur or NR¹³, where R¹³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, orheteroaralkyl groups; R⁸ and R¹³ together may form a substituted orunsubstituted 5 or 6 membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen; m is an integer ranging from 0-6.

The compounds of formula (I) are novel intermediates, useful in thesynthesis of novel antidiabetic compounds of the formula (II), which hasbeen made subject matter of our PCT application entitled “New bicycliccompounds and their use in medicine, process for their preparation andpharmaceutical compositions containing them” filed simultaneously on thesame day.

wherein R¹, R² and R³, R⁴ when attached to the carbon atom, may be sameor different and represent hydrogen, halogen, hydroxy, nitro, cyano,formyl or substituted or unsubstituted groups selected from alkyl,cycloalkyl, alkoxy, to cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy,heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino,dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; one or both of R³ and R⁴ may represent oxo orthioxo group when they are attached to carbon atom; R³ and R⁴ whenattached to nitrogen atom represent hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl,aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen or sulfur; W represents NR¹², —C(═O)—(CR¹⁰R¹¹)_(o)—NR¹²,—O-aryl-(CR¹⁰R¹¹)_(o)—NR¹², where R¹² represents hydrogen or substitutedor unsubstituted group selected from alkyl, aryl or aralkyl groups; o isan integer ranging from 0-6; R¹⁰ and R¹¹ may be same or different andrepresent hydrogen or unsubstituted or unsubstituted group selected formalkyl, alkoxy, aryl or aralkyl group; Ar represents substituted orunsubstituted divalent single or fused aromatic or heterocyclic group;R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen,alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶ forms abond together with R⁵; R⁷ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, 1, heteroaralkylgroups; R⁸ may be hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Y represents oxygen, sulfur or NR⁹, where R⁹represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, orheteroaralkyl groups or NR⁹ represents chiral amine, chiral aminealcohols derived from chiral amino acid; R⁸ and R⁹ together may form asubstituted or unsubstituted 5 or 6 membered cyclic structure containingcarbon atoms, which may optionally contain one or more heteroatomsselected from oxygen, sulfur or nitrogen; m and n are integers rangingfrom 0-6.

The present invention also relates to processes for the preparation ofcompounds of the formula (I) and their use in the preparation ofcompounds of formula (II).

The compounds of general formula (II) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such asatherosclerosis, stroke, peripheral vascular diseases and relateddisorders. These compounds are useful for the treatment ofhyperlipidemia, hyperglycemia, hypercholesterolemia, lowering ofatherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL.The compounds of the present invention can be used for the treatment ofrenal diseases including glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. Thecompounds of general formula (II) are also useful for the treatmentand/or prophylaxis of leptin resistance, impaired glucose tolerance,disorders related to syndrome X such as hypertension, obesity, insulinresistance, coronary heart disease and other cardiovascular disorders.These compounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), inflammatory boweldiseases, osteoporosis, myotonic dystrophy, pancreatitis,arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammationand for the treatment of cancer. The compounds of the present inventionare also useful in the treatment and/or prophylaxis of the above saiddiseases in combination/concomittant with one or more HMG CoA reductaseinhibitors; cholesterol absorption inhibitors; antiobesity drugs;lipoprotein disorder treatment drugs; hypoglycemic agents: insulin;biguanides; sulfonylureas; thiazolidinediones; dual PPARα and γ or amixture thereof.

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases affect thequality of life of millions of people. Therefore, considerable attentionhas been directed towards understanding the etiology ofhypercholesterolemia and hyperlipidemia and development of effectivetherapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations, (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al., (Br. Med. J., 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et al.,Arteriosclerosis 6 (1986) 434-441 have shown by in vitro experiment thatHDL is capable of removing cholesterol from cells. They suggest that HDLmay deplete tissues of excess free cholesterol and transfer it to liver,which is known as reverse cholesterol transport, (Macikinnon et al., J.Biol. chem. 261 (1986), 2548-2552). Therefore, agents that increase HDLcholesterol would have therapeutic significance for the treatment ofhypercholesterolemia and coronary heart diseases (CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyaffects the quality of large population in the world. Insulin resistanceis the diminished ability of insulin to exert its biological actionacross a broad range of concentrations. In insulin resistance, the bodysecretes abnormally high amounts of insulin to compensate for thisdefect; failing which, the plasma glucose concentration inevitablyraises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and is associated with a varietyof abnormalities including obesity, hypertension, hyperlipidemia (J.Clin. Invest., 75 (1985) 809-817; N. Engl. J. Med 317 (1987) 350-357; J.Clin. Endocrinol. Metab., 66 (1988) 580-583; J. Clin. Invest., 68 (1975)957-969) and other renal complications (patent publication No. WO95/21608). It is now increasingly being recognized that insulinresistance and relative hyperinsulinemia have a contributory role inobesity, hypertension, atherosclerosis and type 2 diabetes mellitus. Theassociation of insulin resistance with obesity, hypertension and anginahas been described as a syndrome having insulin resistance as thecentral pathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83(1995) 803-812), whereas the alpha (α) isoform of PPAR (PPARα) mediatesfatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) therebyresulting in reduction of circulating free fatty acid in plasma (CurrentBiol. 5 (1995) 618-621). PPARα agonists have been found useful for thetreatment of obesity (WO 97/36579). It has been recently disclosed thatcompounds which are agonists for both PPARα and PPARγ are suggested tobe useful for the treatment of syndrome X (WO 97/25042). Similar effectbetween the insulin sensitizer (PPARγ agonist) and HMG CoA reductaseinhibitor has been observed which may be useful for the treatment ofatherosclerosis and xanthoma (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, 79 (1994)1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94(1997) 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research 58 (1998) 3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto the PPAR agonist expression lower plasma leptin concentrations.However, it has been recently disclosed that compounds having insulinsensitizing property also possess leptin sensitization activity. Theylower the circulating plasma leptin concentrations by improving thetarget cell response to leptin (WO 98/02159).

PRIOR ART

Few β-phenyl α-hydroxysubstituted propionic acid derivatives have beenreported which have been used as intermediates for the synthesis ofvarious biologically active molecules. Some of such compounds describedin the prior art are outlined below:

i) European Patent Application EP0816316 discloses compound of formula(IIIa)

The compound of formula (IIIa) was further converted to 1,2-ethanediaolderivative of the formula (IIIb)

These 1,2-ethanediaol derivatives are useful intermediates for thepharmaceuticals and agricultural chemicals.ii) Japanese Patent Application JP 10017540 discloses compound offormula (IIIc)

The compound of formula (IIIc) was further converted to a compound offormula (IIId)

iii) U.S. Pat. No. 6,410,576 discloses compound of formula (IIIe)

wherein A₂ is lower alkylene wherein the alkylene can be substitutedphenyl. The compounds of formula were further converted to thiazolidinederivatives of the formula (IIIf)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for reducing blood glucose,lipid levels, lowering cholesterol and reducing body weight withbeneficial effects in the treatment and/or prophylaxis of diseasesrelated to increased levels of lipids, atherosclerosis, coronary arterydiseases, Syndrome-X, impaired glucose tolerance, insulin resistance,insulin resistance leading to type 2 diabetes and diabetic complicationsthereof, for the treatment of diseases wherein insulin resistance is thepathophysiological mechanism and for the treatment of hypertension, withbetter efficacy, potency and lower toxicity, we focused our research todevelop new compounds effective in the treatment of the above mentioneddiseases. Effort in this direction has led to compounds having generalformula (II).

The main objective of the present invention is to provide novel β-phenylα-oxysubstituted propionic acids of formula (I), their derivatives,their analogs, their tautomeric forms and their stereoisomers which areuseful in the synthesis of compounds of formula (II).

Another objective of the present invention is to provide a process forthe preparation of compounds of formula (I), their derivatives, theiranalogs, their tautomers and their stereoisomers.

DETAILED DESCRIPTION OF THE INVENTION

Novel β-phenyl α-oxysubstituted propionic acids having the generalformula (I)

their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their salts, their solvates wherein W represents NR¹²,R¹² represents hydrogen, R¹⁰ and R¹¹ may be same or different andrepresent hydrogen or substituted or unsubstituted group selected formalkyl, alkoxy, aryl or aralkyl group; Ar represents substituted orunsubstituted divalent single or fused aromatic or heterocyclic group;R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl,substituted or unsubstituted aralkyl group or forms a bond together withthe adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen,lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶forms a bond together, with R⁵; R⁷ may be hydrogen or substituted orunsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups;R⁸ may be hydrogen or substituted or unsubstituted groups selected from,alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; Y represents oxygen, sulfur or NR¹³, where R¹³represents hydrogen or substituted or unsubstituted groups selected fromalkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, orheteroaralkyl groups; R⁸ and R¹³ together may form a substituted orunsubstituted 5 or 6 membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen; m is an integer ranging from 0-6.

The novel intermediate of formula (I) where m is 0 and all other symbolsare as defined above may be prepared by reducing the compound of formula(IIIg)

where R⁷, R⁸ and Ar are as defined above may be carried out in thepresence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C,Raney nickel and the like. Mixtures of catalysts may be used. Thereaction may also be conducted in the presence of solvents such asdioxane, acetic acid, ethyl acetate and the like. A pressure betweenatmospheric pressure and 80 psi may be employed. The catalyst may bepreferably 5-10% Pd/C and the amount of catalyst used may range from1-50% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium, iron, tin, samarium in alcohol orsodium amalgam in alcohol, preferably methanol. The hydrogenation may becarried out in the presence of metal catalysts containing chiral ligandsto obtain a compound of formula (I) in optically active form. The metalcatalyst may contain Rhodium, Ruthenium, Indium and the like. The chiralligands may preferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylphenylphosphino) ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like.

The compound of formula (IIIg) may be prepared by reacting the compoundof formula (IIIh)

O₂N—Ar—CHO  (IIIh)

where Ar is as defined above with compound of formula (IIIi)

where R¹³ represents (C₁-C₆)alkyl group and all other symbols are asdefined earlier may be carried out in the presence of a base such asmetal hydride such as NaH or KH; organolithiums such as CH₃Li, BuLi andthe like; alkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the like ormixtures thereof. The reaction may be carried out in the presence ofsolvents such as diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethylacetamide and the like or mixtures thereof. HMPA may be used ascosolvent. The reaction temperature may range from −78° C. to 50° C.,preferably at a temperature in the range of −10° C. to 30° C. Thereaction is more effective under anhydrous conditions.

In yet another embodiment of the present invention, the compound offormula (I) where m is 0 and all other symbols are as defined above maybe prepared by diazotizing the compound of formula (III k) to a compoundof formula au and reducing the compound of formula (III l) to yieldcompound of formula (I). The reaction shown in scheme-III below:

The diazotiaziaon of the compound of the formula (III k) to obtaincompound of formula (III l) may be carried out using diazotizing agentsuch as sodium nitrite, isoamyl nitrite, potassium nitrite, ammoniumnitrite and the like under acidic conditions using acids such assulfuric acid, HCl, acetic acid and the like, in an organic solvent suchas alcohols such as methanol, ethanol, propanol and the like;1,4-dioxane, THF, acetone and the like. Etherifying the residue usingalkyl sulfates such as diethyl sulphate, dimethylsulphate and the likeor alkyl halides such as ethyl iodide, methyliodide and the like, in thepresence of solvents such as hydrocarbons like toluene, benzene and thelike or DMF, DMSO, acetonitrile, THF, methyl isobutyl ketone (MIBK) andthe like, in alkali bases such as sodium carbonate, potassium carbonate,sodium methoxide, sodium hydride, potassium hydride and the like.

The reduction of compound of the formula (IIIl) to yield a compound ofthe general formula (I) may be carried out in the presence of gaseoushydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and thelike. Mixtures of catalysts may be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. The catalyst may be preferably 5-10% Pd/C andthe amount of catalyst used may range from 1-50% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol,preferably methanol. The hydrogenation may be carried out in thepresence of metal catalysts containing chiral ligands to obtain acompound of formula (I) in optically active form. The metal catalyst maycontain Rhodium, Ruthenium, Indium and the like. The chiral ligands maypreferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenyl phenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like.

In yet another embodiment of the present invention, the compound offormula (I) where m is 1-6, and all other symbols are as defined abovemay be prepared by following the process described in scheme-IV below:

The reaction of a compound of the general formula (IIIi) defined abovewith a compound of formula (IVa), to yield compound of formula (IVb) maybe carried out in the presence of a base such as metal hydride like NaHor KH; organolithiums such as CH₃Li, BuLi and the like; alkoxides suchas NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixtures thereof. The reactionmay be carried out in the presence of solvents such as diethyl ether,THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like ormixtures thereof. HMPA may be used as cosolvent. The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C.

The reduction of compound of the formula (IVb) to yield a compound ofthe formula (IVc) may be carried out in the presence of gaseous hydrogenand a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixtures of catalysts may be used. The reaction may also be conducted inthe presence of solvents such as dioxane, acetic acid, ethyl acetate andthe like. A pressure between atmospheric pressure and 80 psi may beemployed. The catalyst may be preferably 5-10% Pd/C and the amount ofcatalyst used may range from 1-50% w/w. The reaction may also be carriedout by employing metal solvent reduction such as magnesium, iron, tin,samarium in alcohol or sodium amalgam in alcohol, preferably methanol.The hydrogenation may be carried out in the presence of metal catalystscontaining chiral ligands to obtain a compound of formula (IVc) inoptically active form. The metal catalyst may contain Rhodium,Ruthenium, Indium and the like. The chiral ligands may preferably bechiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylPhenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like.

The reaction of a compound of general formula (IVc) with a compound offormula (IVd) to provide a compound of formula (I) may be carried outusing solvents such as CH₂Cl₂, CHCl₃, chlorobenzene, benzene, THF, inthe presence of catalyst such as p-toluenesulfonic acid, methanesulfonicacid, TFA, TfOH, BF₃—OEt₂ and the like. The reaction may also be carriedout using activated molecular sieves. The temperature of the reactionmay range from 10° C. to 100° C., preferably at a temperature in therange from 10° C. to 60° C. The imine product initially produce may bereducing using Na(CN)BH₃—HCl.

In yet another embodiment of the present invention, the compound offormula (I) where m is 0 or 1 and all other symbols are as defined abovemay be prepared by diazotizing the compound of formula (IIIk) to acompound of formula (Va), decomposition of compound of formula (Va) to acompound of formula (IIIl) in the presence of alcohol such as R⁷OH andreducing the compound of formula (IIIl) to yield compound of formula(I). The reaction sequence is shown in scheme-V below:

The diazotiaziaon of the compound of the formula (IIIk) where m is 0, R⁶is hydrogen and all other symbols are as defined above, to obtaincompound of formula (Va) may be carried out using diazotizing agent suchas sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitriteand the like in the presence of catalytic amount of carboxylic acid suchas acetic acid, propionic acid and the like, in suitable solvent such aschloroform, chlorobenzene, dichloroethane and the like or a mixturethereof at a temperature in the range of room temperature and refluxtemperature of the solvent employed for a period in the range of 0.5 to16 h.

Decomposing the arylalkyl diazo acetate of the formula (Va) to obtain acompound of formula (IIIl) where R⁷ is as defined earlier excludinghydrogen and all other symbols are as defined earlier can be promoted bya suitable catalyst such as Rh(II) acetate, salt/complex of Cu(I) orRh(II) and the like in the presence of an alcohol of the formula R⁷OH.

The reduction of compound of the formula (IIIl) to yield a compound ofthe general formula (I) where all symbols are as defined earlier may becarried out in the presence of gaseous hydrogen and a catalyst such asPd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts maybe used. The reaction may also be conducted in the presence of solventssuch as dioxane, acetic acid, ethyl acetate and the like. A pressurebetween atmospheric pressure and 80 psi may be employed. The catalystmay be preferably 5-10% Pd/C and the amount of catalyst used may rangefrom 1-50% w/w. The reaction may also be carried out by employing metalsolvent reduction such as magnesium, iron, tin, samarium in alcohol orsodium amalgam in alcohol, preferably methanol. The hydrogenation mayalso be carried out using ammonium formate, cyclohex-1,4-diene type ofhydrogen donor under pd/c conditions using solvents such as methanol,ethanol, ethyl acetate and the like.

In yet another embodiment of the present invention, the compound offormula (I) in its enantiomerically pure form, where m is 0, R⁵=R⁶=H andall other symbols are as defined above may be prepared by following theprocess described in scheme-VI below:

The diazotization of the compound of the formula (VIa) where all symbolsare as defined above to obtain compound of formula (VIb) may be carriedout by using diazotizing agent such as sodium nitrite, isoamyl nitrite,potassium nitrite, ammonium nitrite and the like under aqueous acidicconditions using acids such as sulfuric acid, HCl, acetic acid and thelike, in an organic solvent such as alcohols such as methanol, ethanol,propanol and the like; 1,4-dioxane, THF, acetone and the like.

One pot esterification and etherification of compound of general formula(VIb) to a compound of general formula (VIc) may be carried by initialdi deprotonation of (VIb) using a suitable base such as NaH, KH, KOH orlike, in a suitable solvent such as toluene, benzene, diethylether, THF,DMF, DME HMPA, and like, followed by treatment with alkyl halide such asethyl iodide or methyl iodide and like. Other alkylating agents such asEt₃O⁺BF₄ ⁻, Me₃O⁺BF₄ ⁻, dialkylsulfate may also be used. Reactiontemperature may vary from 0° C. to 100° C.

Nitration of the compound of formula (VIc) to a compound of formula(VId) where n is 0 and all other symbols are as defined above, may becarried out using nitrating agents such as fuming nitric acid, N₂O₅, amixture of conc. Nitric acid and conc. Sulfuric acid or a mixture ofnitric acid and acetic anhydride in the presence of a solvent or underneat condition at a temperature in the range of −10° C. to roomtemperature for a period in the range of 0.5 to 4 h. (Ref: Org. Synth.Col. Vol. I, 396)

Reduction of compound of the formula (VId) to a compound of formula (I),may be carried out in the presence of gaseous hydrogen or hydrogendonors such as ammonium formate, cyclohex-1,4-diene and the like and acatalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixturesof catalysts may be used in the presence of solvents such as methanol,ethanol, dioxane, acetic acid, ethyl acetate and the like. A pressurebetween atmospheric pressure and 80 psi may be employed. The catalystmay be preferably 5-10% Pd/C and the amount of catalyst used may rangefrom 1-50% w/w. Alternatively, the reaction may also be carried out byemploying metal solvent reduction such as magnesium, iron, tin,samarium, indium, sodium amalgam in alcohol, or other suitable solventspreferably methanol.

In yet another embodiment of the present invention, the compound offormula (I) in its enantiomerically pure form, where m is 0, R⁵=R⁶=H andall other symbols are as defined above may be prepared by following theprocess described in scheme-VII below:

The diazotization of the compound of formula (VIIa) where all symbolsare as defined above to obtain a compound of formula (VIIb) may becarried out using diazotizing agents such as sodium nitrite, isoamylnitrite, potassium nitrite, ammonium nitrite and the like under aqueousacidic conditions using acids such as sulfuric acid, hydrochloric acid,acetic acid and the like, in presence of an optional co solvent likealcohols such as methanol, ethanol, propanol and the like; or etherssuch as 1,4-dioxane, THF, and the like; or ketones such as acetone,methyl ethyl ketone and the like.

Esterification of the compound of formula (VIIb) to a compound offormula (VIIc) may be done using an appropriate alcohol of formula R⁸—OHwhere R⁸ represents lower alkyl groups such as methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl and the like in presence of suitablecatalyst such as, conc. sulfuric acid, dry HCl, BF₃—OEt₂, and the like.The reaction may be carried out at reflux temperature of the alcoholemployed. Alternatively reagents like diazomethane or Et₃O⁺BF₄ ⁻ orMe₃O⁺BF₄ ⁻ and the like may also be used for esterification.

Selective O-alkylation of the compound of formula (VIIc) to the compoundof formula (VIId) may be done using alkyl sulfates such as diethylsulfate, dimethyl sulfate and the like or alkyl halides such as ethyliodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyliodide and the like, in solvents such as hydrocarbons like toluene,benzene and the like or acetonitrile, tetrahydro furan, dimethylformamide, dimethyl sulfoxide, and the like, in the presence ofmolecular sieves and alkali bases such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium methoxide, sodium hydride, potassiumhydride, sodium or potassium hydroxide and the like. Heavy metal oxidessuch as Ag₂O, PbO, HgO and the like may be of particular use to carryout alkylation when alkyl halides are used as alkylation reagent. Phasetransfer catalysts such as tetraalkylammonium hydroxide ortetraalkylammonium halides such as tetrabutylammonium chloride,tetrabutylammonium bromide and the like may also be employed.

Reduction of compound of the formula (VIId) to a compound of formula(I), may be carried out in the presence of gaseous hydrogen or hydrogendonors such as ammonium formate, cyclohex-1,4-diene and the like and acatalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixturesof catalysts may be used in the presence of solvents such as methanol,ethanol, dioxane, acetic acid, ethyl acetate and the like. A pressurebetween atmospheric pressure and 80 psi may be employed. The catalystmay be preferably 5-10% Pd/C and the amount of catalyst used may rangefrom 1-50 w/w. Alternatively, the reaction may also be carried out byemploying metal solvent reduction such as magnesium, iron, tin,samarium, indium, sodium amalgam in alcohol, or other suitable solventspreferably methanol.

In yet another embodiment of the present invention, the compound offormula (I) in its enantiomerically pure form, where m is 0, R⁵=R⁶=H andall other symbols are as defined above may be prepared by following theprocess described in scheme-VIII below:

The diazotization of the compound of formula (VIIa) where all symbolsare as defined above to obtain a compound of formula (VIIb) may becarried out using diazotizing agents such as sodium nitrite, isoamylnitrite, potassium nitrite, ammonium nitrite and the like under aqueousacidic conditions using acids such as sulfuric acid, hydrochloric acid,acetic acid and the like, in presence of an optional co solvent likealcohols such as methanol, ethanol, propanol and the like; or etherssuch as 1,4-dioxane, THF, and the like; or ketones such as acetone,methyl ethyl ketone and the like.

Esterification of the compound of formula (VIIb) to a compound offormula (VIIc) may be done using an appropriate alcohol of formula R⁸—OHwhere R⁸ represents lower alkyl groups such as methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl and the like in presence of suitablecatalyst such as, conc. sulfuric acid, dry HCl, BF₃—OEt₂, and the like.The reaction may be carried out at reflux temperature of the alcoholemployed. Alternatively reagents like diazomethane or Et₃O⁺BF₄ ⁻ orMe₃O⁺BF₄ ⁻ and the like may also be used for esterification.

Reduction of compound of the formula (VIIc) to a compound of formula(VIIIa), may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixture of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure to 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w. Alternatively, the reaction may also becarried out by employing metal solvent reduction such as magnesium,iron, tin, samarium, indium, sodium amalgam in alcohol, or othersuitable solvents preferably methanol.

N,N-dibenzylation of the compound of formula (VIIIa) to the compound offormula (VII %) may be done using benzyl halides such as benzyl bromide,benzyl chloride and the like in solvents such as hydrocarbons liketoluene, benzene and the like or acetonitrile, tetrahydro furan,dimethyl formamide, dimethyl sulfoxide, and the like, in the presence ofalkali bases such as sodium carbonate, potassium carbonate, sodium orpotassium hydroxide and the like. Phase transfer catalysts such astetraalkylammonium hydroxide or tetraalkylammonium halides such astetrabutylammonium chloride, tetrabutylammonium bromide and the like mayalso be employed. The reaction may be carried out in the range of roomtemperature to the reflux temperature of the solvent employed.

Hydrolysis of the compound of the formula (VIIIb) to the compound offormula (VIIIc) using aqueous alkali metal bases such as lithiumcarbonate, sodium carbonate, potassium carbonate or potassiumbicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxideand the like, in suitable co-solvents such as methanol, ethanol, THF andlike or mixtures thereof. The reaction time may range from 0.5 h to 24h, preferably 0.5 h to 3-4 h and reaction temperature may range from 0°C. to 80° C.

One pot esterification and etherification of the compound of the formula(VIIIc) to the compound of formula (VIIId) where R⁵=R⁶, may be done bytreating with bases such as sodium hydride, potassium hydride, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonateand the like, in solvents such as hydrocarbons like toluene, benzene andthe like, dialkyl ethers such as diethyl ether, tetrahydro furan and thelike or dimethyl formamide, HMPA followed by treatment with alkylhalides such as ethyl iodide, methyl iodide, n-propyl iodide, n-propylbromide, isopropyl iodide and the like, or alkyl sulfates such asdiethyl sulfate, dimethyl sulfate and the like or alkylating agents suchas Et₃O⁺BF₄ ⁻, Me₃O⁺BF₄ ⁻ and the like. The reaction time may range from2 h to 20 h and reaction temperature may range from 0° C. to 80° C.

Debenzylation of the compound of the formula (VIIId) to the compound offormula (I) may be carried out in the presence of gaseous hydrogen orhydrogen donors such as ammonium formate, cyclohex-1,4-diene and thelike and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.Mixture of catalysts may be used in the presence of solvents such asmethanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 1-50% w/w.

Particularly useful compounds according to the present inventioninclude:

-   (±) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (+) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (−) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (±) Ethyl    2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate-   (+) Ethyl    2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate-   (−) Ethyl    2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate-   (±) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate-   (+) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate-   (−) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate-   (±) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (+) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (−) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate-   (±) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate-   (+) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate-   (−) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate-   (±) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate-   (+) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate-   (−) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate

The compounds of the present invention can be converted to the compoundsof the formula (II) which includes:

-   (±) Ethyl    3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (+) Ethyl    3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (−) Ethyl    3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (±)    3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (+)    3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (−)    3-[4-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (±) Ethyl    3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;-   (+) Ethyl    3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;-   (−) Ethyl    3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate;-   (±)    3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (+)    3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (−)    3-[4-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (±) Methyl    2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;-   (+) Methyl    2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;-   (−) Methyl    2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate;-   (±)    2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic    acid or its salts;-   (+)    2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic    acid or its salts;-   (−)    2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic    acid or its salts;-   (±) Methyl    3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;-   (−) Methyl    3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoate;-   (±)    3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (+)    3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (−)    3-[4-{5-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (±) Methyl    3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (−) Methyl    3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate;-   (±)    3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (+)    3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (−)    3-[3-{3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (±) Methyl    3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate;-   (−) Methyl    3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate;-   (±)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (+)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (−)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts;-   (±) Methyl    2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (+) Methyl    2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (−) Methyl    2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (±) Methyl    2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (+) Methyl    2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (−) Methyl    2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate;-   (±)    2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)    benzyl}aminophenyl]propanoic acid or its salts;-   (+)    2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)    benzyl}aminophenyl]propanoic acid or its salts;-   (−)    2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic    acid or its salts;-   (±)    2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic    acid or its salts;-   (+)    2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)    benzyl}aminophenyl]propanoic acid or its salts;-   (−)    2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)    benzyl}aminophenyl]propanoic acid or its salts;-   (±) Ethyl    2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;-   (+) Ethyl    2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;-   (−) Ethyl    2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate;-   (±)    2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic    acid or its salts;-   (+)    2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic    acid or its salts;-   (−)    2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic    acid or its salts;-   (±) Ethyl    2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;-   (+) Ethyl    2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;-   (−) Ethyl    2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate;-   (±)    2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic    acid or its salts;-   (+)    2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic    acid or its salts;-   (−)    2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic    acid or its salts;-   (±) Methyl    2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;-   (+) Methyl    2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;-   (−) Methyl    2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate;-   (±)    2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[1)][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic    acid or its salts;-   (+)    2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic    acid or its salts;-   (−)    2-Ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic    acid or its salts;-   (±) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (+) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (−) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (±) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (+) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (−) Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (±)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (+)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (−)    3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (±) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (+) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (−) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (±)    3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (+)    3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (−)    3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (±) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (+) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (−) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (±)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (+)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (−)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (±) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (+) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (−) Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (±)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (+)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (−)    3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid or its salts-   (±) Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (+) Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (−) Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-ethoxypropanoate-   (±)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (+)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (−)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic    acid or its salts-   (±) Ethyl    (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (+) Ethyl    (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (−) Ethyl    (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (±)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   (+)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   (−)    3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   (±) Ethyl    2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoate-   (+) Ethyl    2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoate-   (−) Ethyl    2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoate-   (±)    2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoic acid and its salts-   (+)    2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoic acid and its salts-   (−)    2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]propanoic acid and its salts-   (±) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (+) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (−) Ethyl    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)    propylamino}phenyl]-2-methoxypropanoate-   (±)    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   (+)    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   (−)    3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic    acid and its salts-   [2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;-   [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;-   [2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide-   [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide-   [2S,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide    hydrochloride salt;-   [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide    hydrochloride salt;

The novel antidiabetic compounds of formula (II) and process forpreparing them are described and claimed in our PCT application entitled“New bicyclic compounds and their use in medicine, process for theirpreparation and pharmaceutical compositions containing them” filedsimultaneously on the same day.

It is appreciated that in any of the above mentioned reactions, anyreactive group in the substrate molecule may be protected according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are tertiarybutyl dimethyl silylchloride,methoxymethyl chloride etc, to protect hydroxyl group, N-Boc, N-Cbz,N-Fmoc etc, for protection of amino group, acetal protection foraldehyde, ketal protection for ketone and the like. The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR⁸represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, amino acids, amino alcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

Example 1 Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate

Step (i)

Wittig salt from triethyl 2-ethoxyphosphonoacetate (26.5 g, 1.5 eq, 99.3mmol) and NaH (50% in oil) (5.3 g, 2 eq, 132.4 mmol) was prepared in THF(350 ml) at 0° C. To this solid 4-nitrobenzaldehyde (10 g, 1 eq, 66.2mmol) was added in portions at 0° C. and the resulting solution wasstirred at RT for 16 h. The reaction mixture was diluted with ethylacetate and washed with aqueous NH₄Cl. The crude contains ethyl4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (11 g).

Step (ii)

Ethyl 4-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenatedusing Pd (10%)/C—H₂ (60 psi) (11 g) in ethyl acetate (150 ml) at RT andchromatographed using ethyl acetate/hexane to yield the title compoundas viscous oil (9.41 g, yield 60%).

¹H NMR (200 MHz, CDCl₃) δ: 1.16 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz,3H), 2.90 (d, J=6.3 Hz, 2H), 3.30 (bs, 2H, NH₂), 3.35 (m, 1H), 3.55 (m,1H), 3.94 (t, J=6.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 6.62 (d, J=8.3 Hz,2H), 7.03 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3372, 1738.

Mass m/z (CI): 238 (M+1), 192 (M-OC₂H₅).

Example 2 Ethyl2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate

Step (i)

A mixture of ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (5 g, 1 eq, 21mmol) obtained in preparation 1, heptylbromide (18.8 g, 5 eq, 105 mmol),and anhydrous K₂CO₃ (14.5 g, 5 eq, 105 mmol), was heated at 70° C. inDMF (100 ml), for 16 h. The reaction mixture was diluted with ethylacetate, washed with water and brine. The residue was chromatographedusing a mixture of ethyl acetate and hexane as diluent to affordmonoheptylated product as thick liquid (3.85 gm, yield 55%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 15H),1.42-1.68 (m, 2H), 2.90 (d, J=6.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H),3.22-2.42 (m, 1H), 3.44-3.64 (m, 1H), 3.94 (t, J=6.8 Hz, 1H), 4.1 (q,J=7.0 Hz, 2H), 6.55 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3396, 1747.

Mass m/z (CI): 335 (M+1), 290 (M-OC₂H₅).

Step (ii)

The mono heptylated product (3 g, 1 eq, 8.98 mmol) obtained in step (i)was treated with excess dibromoethane (10 eq) in presence of anhydrousK₂CO₃ (3.72 g, 3 eq, 27 mmol), in DMF (40 ml), and heated at 70° C. for16 h. The reaction mixture was diluted with ethyl acetate, washed withwater and brine. The residue was chromatographed using a mixture ofethyl acetate and hexane as diluent to yield ethyl2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate asthick liquid (1.98 g, yield 50%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 14H),1.42-1.68 (m, 2H), 2.90 (d, J=6.6 Hz, 2H), 3.28 (t, J=7.3 Hz, 2H),3.30-3.45 (m, 3H), 3.50-3.70 (m, 3H), 3.96 (t, J=6.8 Hz, 1H), 4.17 (q,J=7.0 Hz, 2H), 6.57 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 1747.

Mass m/z (CI): 442 (M(⁷⁹Br)+1), 444 (M(Br⁸¹)+1).

Example 3 Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate

Step (i)

Methyl 3-[4-formylphenyl]-2-ethoxypropanoate (2 g, 1 eq, 8.51 mmol)obtained in preparation 5, heptylamine (978 mg, 1 eq, 8.51 mmol) andcat. amount of p-TsOH.H₂O were taken in DCM (40 ml), along with fewpieces of activated molecular sieves (4 A). The reaction mixture wasfiltered through celite after 24 h, at RT and the filtrate was dilutedwith DCM and was washed with aqueous sodium bicarbonate and dried overanhydrous sodium sulfate to yield crude methyl2-ethoxy-3-[4-(N-heptyliminomethyl)phenyl]propanoate

Step (ii)

The crude methyl 2-ethoxy-3-[4-(N-heptyliminomethyl)phenyl]propanoateobtained in step (i) above (2.95 g), was dissolved in methanol (40 ml),and treated with conc. HCl (850 μl, 1 eq, 8.51 mmol) and sodiumcyanoborohydride (535 mg, 1 eq, 8.51 mmol) at 0° C. The progress of thereaction was monitored by TLC. After 2-3 h, the reaction mixture wasdiluted with ethyl acetate, washed with aqueous sodium bicarbonate anddried over anhydrous sodium sulfate. The residue was chromatographedusing methanol and chloroform to afford the title compound (1.71 g,yield 60%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 0.86 (bt, J=6.3 Hz, 3H), 1.14 (t, J=6.8 Hz,3H), 1.20-1.40 (m, 9H), 1.50-1.70 (m, 2H), 2.60 (t, J=7.4 Hz, 2H), 2.98(d, J=6.3 Hz 2H), 3.22-3.41 (m, 1H), 3.48-3.67 (m, 1H), 3.71 (s, 3H),3.89 (s, 2H), 4.02 (t, J=6.3 Hz, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.30 (d,J=7.8 Hz, 2H).

IR (neat) cm⁻¹: 3500 (br), 1748.

Mass m/z (CI): 336 [M+1].

Example 4 Methyl 2-ethoxy-3-(4-aminophenyl)propanoate

Ethyl 4-nitro-2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol) obtained in step(i) of preparation 1, was treated with activated magnesium turnings (18g, 20 eq, 754 mmol) in dry methanol (400 ml). The reaction mixture wasrefluxed for 2-3 h, and allowed to stir at room temperature for 16 h.The reaction mixture was diluted with ethyl acetate and quenched withcold aqueous ammonium chloride. The organic layer was washed with waterand brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound as liquid (6 g, yield 72%).

¹H NMR (200 MHz, CDCl₃) δ: 1.64 (t, J=6.8 Hz, 3H), 2.90 (d, J=6.3 Hz,2H), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (s, 3H), 3.96 (t, J=6.8Hz, 1H), 6.61 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3350 (br), 1735.

Mass m/z (CI): 224 [M+1].

Example 5 Methyl 2-ethoxy-3-(3-aminophenyl)propanoate

Step (i)

Wittig salt from triethyl 2-ethoxyphosphonoacetate (34.3 ml, 2 eq, 132mmol) and NaH (50% in oil) (6.28 g, 2 eq, 132 mmol) was prepared inTI-IF (350 ml) at 0° C. To this solid 3-nitrobenzaldehyde (10 g, 1 eq,66 mmol) was added in portions at 0° C. The resulting solution wasstirred at RT for 16 h. The reaction mixture was diluted with ethylacetate and washed with aqueous NH₄Cl. The crude contains ethyl4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (15 g, yield86%).

Step (ii)

The crude compound (15 g, 1 eq, 56.6 mmol) obtained in step (i) wasdissolved in methanol (250 ml). To this ammonium formate (35.6 g, 10 eq,566 mmol) and 10% Pd/C (40 g) was added and the reaction mixture wasstirred at RT for 16 h. The catalyst was filtered and the methanol wascondensed on rotavapour. The reaction mixture was diluted with ethylacetate and washed with water and brine. The residue was chromatographedto yield methyl 2-ethoxy meta amino cinnamate as (E) and (Z) isomers (10g, yield 75%).

Step (iii)

Methyl 2-ethoxy meta amino cinnamate (10 g, 1 eq, 42.5 mmol) obtained instep (ii) was treated with magnesium (20.4 g, 20 eq, 850 mmol) and drymethanol (500 ml). The reaction mixture was refluxed for 2-3 h, andallowed to stir at room temperature for 16 h. The reaction mixture wasdiluted with ethyl acetate and quenched with cold aqueous ammoniumchloride. The organic layer was washed with water and brine. The residuewas chromatographed using ethyl acetate and hexane to afford the titlecompound as viscous liquid (8.06 g, yield 80%):

¹H NMR (200 MHz, CDCl₃) δ: 1.15 (t, J=6.8 Hz, 3H), 2.96 (d, J=6.9 Hz,2H), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (s, 3H), 4.01 (t, J=6.4Hz, 1H), 6.50-6.62 (aromatics, 3H), 7.06 (t, J=7.8 Hz, 1H).

IR (neat) cm⁻¹: 3360, 1738.

Mass m/z (CI): 224 (M+1).

Example 6 (S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propionate

Step (i)

To a solution of (S)-(4-nitrophenyl) alanine (10 g, 47.6 mmol) in amixture of water (50 mL), H₂SO₄ (1M, 60 mL) and acetone (150 mL) at −5°C., was added under stirring, a solution of sodium nitrite (9.85 g,142.8 mmol) in water (40 mL) drop wise over a period of 30 min. Thereaction mixture was stirred at −5 to 0° C. for another 1.5 h, followedby stirring at room temperature for 16 h. Acetone was removed and thenthe reaction mixture was diluted with 500 mL ethyl acetate. Organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated. The crude mass was purified by crystallization fromisopropyl acetate (9.0 g, 96%).

Mp: 134-136° C.

[α]_(D): −25° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 3.04 (dd, J=14, 7.8 Hz, 1H), 3.24 (dd, J=14, 4, Hz,1H), 4.39 (dd, J=7.3, 4.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 2H), 8.16 (d,J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 3485, 3180, 2927, 1715, 1515, 1343.

Mass m/z (CI): 212 (M+1).

Step (ii)

(S)-2-Hydroxy-3-(4-nitrophenyl)propionic acid (9.0 g, 42.6 mmol),obtained from step (i) above, was dissolved in dry EtOH (300 mL). Tothis solution was added conc. H₂SO₄ (326 mL, 5.9 mmol), and refluxed for5 to 6 h. The reaction mixture was neutralized with aqueous sodiumbicarbonate. Ethanol was condensed on rotavapor, and the residue wasdissolved in ethyl acetate. Organic layer was washed with aqueous sodiumbicarbonate, water, brine, and then dried over anhydrous Na₂SO₄, andconcentrated. Desired product was obtained from the crude mass bycrystallizing from diisopropylether (8.0 g, 78.5%).

Mp: 74-76° C.

[α]_(D): −13° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.30 (t, J=7 Hz, 3H), 3.06 (dd, J=14, 7, Hz, 1H), 3.25(dd, J=14, 4.3, Hz, 1H), 4.25 (q, J=7 Hz, 2H), 4.25 (dd, J=7, 4.3 Hz,1H), 7.42 (d, J=8.7 Hz, 2H), 8.16 (d, J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 3432, 2924, 1736, 1518, 1347.

Mass m/z (CI): 240 (M+1).

Step (iii)

To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (4.77 g,19.95 mmol), obtained in step ii above, molecular sieves (4 A) (5.0 g)and powdered Ag₂O (13.8 g, 59.8 mmol) in dry acetonitrile (100 mL), wasadded ethyl iodide (6.4 mL, 79.8 mmol) at room temperature. The reactionmixture was heated at 60° C. for 16 h. The reaction mixture was filteredthrough celite, and concentrated. The crude mass was chromatographedusing ethyl acetate and hexanes to obtain the desired product as viscousliquid (3.5 g, 67% isolated yield). Unreacted starting material wasrecovered (900 mg) which could be reused.

[α]_(D): −26° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.15 (t, J=7 Hz, 3H); 1.26 (t, J=7.1 Hz, 3H); 3.10 (d,J=3.8 Hz, 1H); 3.13 (s, 1H); 3.16-3.35 (m, 1H); 3.45-3.65 (m, 1H); 4.03(dd, J=7.5, 5.4 Hz, 1H); 4.21 (q, J=7.2 Hz, 2H); 7.43 (d, J=8.6 Hz, 2H);8.15 (d, J=8.6 Hz, 2H).

IR (neat) cm⁻¹: 2980, 1747, 1604, 1521, 1347.

Mass m/z (CI): 268 (M+1).

Step (iv)

(S)-Ethyl 2-ethoxy-3-(4-nitrophenyl)propionate (6.0, 25.3 mmol),obtained in step (iii) above, was dissolved in dry methanol (100 mL). Tothis solution was added 10% Pd/C (2.0 g), and was hydrogenated usinghydrogen gas (20 psi) for 3-4 h. The reaction mixture was filteredthrough celite, and the filtrate was concentrated to provide a syrupymass. The product was obtained in quantitative yield.

[α]_(D): −14.2° (c 1.0, MeOH).

Chiral HPLC: >98% ee.

¹H NMR (CDCl₃) δ: 1.16 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 2.90(d, J=6.3 Hz, 2H), 3.30 (bs, 2H, NH₂), 3.24-3.42 (m, 1H), 3.50-3.70 (m,1H), 3.94 (t, J=6.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 6.62 (d, J=8.3 Hz,2H), 7.03 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 3372, 1738.

Mass m/z (CI): 238 (M+1), 192 (M-OC₂H₅).

Example 7 (S)-Ethyl 2-methoxy-3-(4-aminophenyl)propionate

Step (i)

To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (12.5 g,52.3 mmol), obtained in step (ii) of preparation 20, and powdered Ag₂O(36.3 g, 157 mmol) in dry acetonitrile (260 mL) was added methyl iodide(13 mL, 209.2 mmol) at room temperature. Activated molecular sieves (4A) (12.5 g) were added and then the reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was filtered through celite,and concentrated. The crude mass was chromatographed using ethyl acetateand hexanes to obtain the desired product as viscous liquid (10.0 g,75%).

[α]_(D): −30.1° (c 1.0, MeOH)

¹H NMR (CDCl₃) δ: 1.24 (t, J=7.1 Hz, 3H); 3.09 (d, J=5.4 Hz, 1H); 3.12(d, J=2.7 Hz, 1H); 3.35 (s, 3H); 3.96 (dd, J=7.5, 5.1 Hz, 1H); 4.19 (q,J=7.1 Hz, 2H); 7.39 (d, J=8.6 Hz, 2H); 8.13 (d, J=8.6 Hz, 2H).

IR (neat) cm⁻¹: 2995, 1747, 1604, 1521, 1343.

Mass m/z (CI): 254 (M+1).

Step (ii)

(S)-Ethyl 2-methoxy-3-(4-nitrophenyl)propionate (8.0, 31.6 mmol),obtained in step (i) above, was dissolved in dry methanol (200 mL). Tothis solution was added 10% Pd/C (2.5 g), and hydrogenated usinghydrogen gas (20 psi) for 3-4 h. The reaction mixture was filteredthrough celite, and concentrated to a syrupy mass. After columnchromatography using ethyl acetate/hexanes the desired product wasisolated as thick liquid (7.0 g, quantitative).

[α]_(D): −14.1° (c 1.0, MeOH).

Chiral HPLC: >98% ee.

¹H NMR (CDCl₃) δ: 1.23 (t, J=7.2 Hz, 3H), 2.91 (d, J=6.1 Hz, 2H), 3.30(bs, 2H, NH₂), 3.34 (s, 3H), 3.88 (t, J=6.2 Hz, 1H), 4.17 (q, J=7.2 Hz,2H), 6.62 (d, J=8.3 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H).

IR (neat) cm⁻¹: 3372, 2985, 2932, 1739, 1627, 1519.

Mass m/z (CI): 223 (M), 234 (M+1), 192 (M-OMe).

Example 8 Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate

Step (i):

4-nitrophenylalanine (5 g, 1 eq, mmol) was added in portions to asolution of dry ethanol (mL) and thionylchloride (mL) at −5° C. It wasstirred at that temperature for another one hour, followed by stirringat RT for 16 h. The reaction mixture was condensed on rotavapour,azeotroped with toluene, and then dried over high vacuum pump to obtain4-nitrophenylalanine ethyl ester hydrochloride as white solid(quantitative yield).

Step (ii):

4-nitrophenylalanine ethyl ester hydrochloride (2 g, 1.0 eq, 7.28 mmol)obtained in step (i) was dissolved in ethyl acetate (150 mL). To thatNa₂CO₃ (386 mg, 0.5 eq, 3.64 mmol) was added and was stirred for 15 min.The reaction mixture was washed with aq. NaHCO₃. The organic layer wasdried (Na₂SO₄), and condensed to obtain 4-nitrophenylalanine ethyl esteras thick oil (1.55 g, 89%).

Step (iii):

4-nitrophenylalanine ethyl ester (1.55 g, 1.0 eq, 6.51 mmol), obtainedin step (ii) above was dissolved in chloroform (33 mL). To that glacialacetic acid (20 μL, 0.05 eq, 0.33 mmol), and isoamylnitrite (958 μL, 1.1eq, 7.16 mmol) were added and the reaction mixture was heated at refluxfor 30 min. The reaction mixture was diluted with chloroform, and waswashed with aq. NaHCO₃. The organic layer was dried (Na₂SO₄) andcondensed (caution !) to a yellowish liquid.

Step (iv):

The liquid (1.54 g, 1.0 eq, 6.18 mmol) thus obtained in step (iii), wasdissolved in dry isopropanol (31 mL), and to that catalytic amount ofRh₂(OAc)₄.2H₂O (38 mg, 0.02 eq, 0.12 mmol) was added and the reactionmixture was stirred at room temperature for 16 h. Isopropanol wascondensed, and the reaction mixture was diluted with ethyl acetate. Theorganic layer was washed with water and brine, dried (Na₂SO₄), andconcentrated. Column chromatography, using ethyl acetate and hexanes,provided the desired compound ethyl2-isopropoxy-3-(4-nitrophenyl)propionate (1.25 g, 61% overall).

¹H NMR (200 MHz, CDCl₃) δ: 0.92 (d, J=5.8 Hz, 3H), 1.16 (d, J=5.8 Hz,3H), 1.27 (t, J=7.4 Hz, 3H), 3.00-3.10 (m, 2H), 3.52 (quintet, 1H); 4.08(dd, J=8.7 and 4.8 Hz, 1H), 4.21 (q, J=7.4 Hz, 2H), 7.43 (d, J=8.7 Hz,2H), 8.16 (d, J=8.7 Hz, 2H).

IR (neat) cm⁻¹: 2975, 1747, 1602, 1522, 1347.

Mass m/z (CI): 282 [M+1]

Step (v):

Ethyl 2-isopropoxy-3-(4-nitrophenyl)propionate (1.52 g, 5.4 mmol)obtained in step (v) was hydrogenated under 10 psi pressure of molecularhydrogen using 10% Pd/C (700 mg) as catalyst in ethyl acetate (200 mL)at room temperature for 3-4 h. The desired product was isolated afterfiltering the reaction mixture and concentrating the filterate underreduced pressure. Column chromatography of the crude mass using ethylacetate and hexanes provided the desired compound ethyl2-isopropoxy-3-(4-aminophenyl)propionate (1.16 g, 86% overall).

¹H NMR (200 MHz, CDCl₃) δ: 0.97 (d, J=5.8 Hz, 3H), 1.15 (d, J=5.8 Hz,3H), 1.23 (t, J=7.0 Hz, 3H), 2.80-2.95 (m, 2H), 3.49 (quintet, 1H); 3.98(dd, J=8.1 and 5.7 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 6.61 (d, J=8.3 Hz,2H), 7.03 (d, J=8.3 Hz, 2H).

IR (neat) cm⁻¹: 3455, 3371, 2975, 2929, 1737, 1626, 1519.

Mass m/z (CI): 252 [M+1]

Representative examples wherein compounds of the formula (I) have beenconverted to compounds of formula (II)

Example 9 Ethyl3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Step (i):

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydroussodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) washeated at 70° C. for 16 h. The reaction mixture was diluted with ethylacetate and washed with water and brine. The residue was chromatographedusing ethyl acetate and hexane to yield3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide as liquid mass(2.6 g, 47%).

¹H NMR (200 MHz, CDCl₃) δ: 2.10-2.30 (m, 2H), 3.37 (t, J=4.4 Hz, 2H),3.40-3.56 (m, 4H), 4.25 (t, J=4.3 Hz, 2H), 6.60-6.90 (m, aromatics, 4H).

Mass m/z (CI): 255 (M(⁷⁹Br)), 256 (M(⁷⁹Br)+1), 257 (M(Br⁸¹)), 258(M(Br⁸¹)+1).

Step (ii):

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2 g, 1 eq, 8.4 mmol)obtained in example 1,3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (2.36 g, 1.1 eq, 9.3 mmol), obtained in step (i) above, andanhydrous K₂CO₃ (3.5 g, 3 eq, 25 mmol), were heated at 70° C. in DMF (40ml) for 24 h. The reaction mixture was diluted with ethyl acetate,washed with water and brine. The residue was chromatographed using amixture of ethyl acetate and hexane as eluent to afford the titlecompound as a viscous liquid (1.04 g, yield 30%).

¹H NMR (200 MHz, CDCl₃) 1.17 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H),1.92 (q, J=7.0 Hz, 2H), 2.90 (d, J=6.8 Hz, 2H), 3.20 (t, J=7.0 Hz, 2H),3.22-3.41 (m, 5H), 3.45-3.62 (m, 1H), 3.95 (t, J=6.4 Hz, 1H), 4.05-4.37(m, 4H), 6.65 (d, J=8.3 Hz, 2H), 6.61-6.85 (m, 4H), 7.05 (d, J=8.3 Hz,2H).

IR (neat) cm⁻¹:3396 (br), 1740.

Mass m/z (CI): 413 (M+1).

Example 10 Ethyl3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate

3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (185 mg, 1.24 mmol), ethyl2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate (500mg, 1 eq, 1.13 mmol) obtained in example 2, and anhydrous K₂CO₃ (468 mg,3 eq, 3.39 mmol), were heated at 70° C. in DMF (6 ml) for 16 h. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using a mixture of ethyl acetateand hexanes as diluent to afford the title compound as thick liquid (363mg, yield 63%).

¹H NMR (200 MHz, CDCl₃) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 14H),1.42-1.68 (m, 2H), 2.92 (d, J=6.8 Hz, 2H), 3.25 (t, J=7.3 Hz, 2H),3.30-3.45 (m, 1H), 3.50-3.70 (m, 3H), 3.97 (t, J=6.6 Hz, 1H), 4.08 (t,J=7.3 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 6.57 (d, J=8.3 Hz,2H), 6.99 (s, 4H), 7.10 (d, J=8.0 Hz, 2H).

IR (neat) cm⁻¹: 1747.

Mass m/z (CI): 511 (M+1).

Example 11 Methyl3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Step (i):

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydroussodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) washeated at 70° C. for 16 h. The reaction mixture was diluted with ethylacetate and washed with water and brine. The residue was chromatographedusing ethyl acetate and hexane to yield3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide as liquid mass(2.6 g, 47%).

¹H NMR (200 MHz, CDCl₃) δ: 2.10-2.30 (m, 2H), 3.37 (t, J=4.4 Hz, 2H),3.40-3.56 (m, 4H), 4.25 (t, J=4.3 Hz, 2H), 6.60-6.90 (m, aromatics, 4H).

Mass m/z (CI): 255 (M(⁷⁹Br)), 256 (M(⁷⁹Br)+1), 257 (M(Br⁸¹)), 258(M(Br⁸¹)+1).

Step (ii):

Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (200 mg, 1 eq, 0.89 mmol)obtained in example5,3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (253 mg, 1.1eq, 0.98 mmol) obtained in step (i) above, and anhydrous Na₂CO₃ (285 mg,3 eq, 2.68 mmol) were heated at 70° C. in DMF (5 ml), for 24 h. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine. The residue was chromatographed using ethyl acetate and hexane toafford the title compound (304 mg, yield 86%) as viscous liquid.

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7 Hz, 3H), 1.98 (q, J=7 Hz, 2H),2.92 (d, J=6.8 Hz, 2H), 3.19 (t, J=7 Hz, 2H), 3.22-3.41 (m, 5H),3.45-3.62 (m, 1H), 3.70 (s, 3H), 4.02 (t, J=6.4 Hz, 1H), 4.22 (t, J=4.3Hz, 2H), 6.40-6.82 (m, aromatics, 6H), 6.75 (d, J=7.8 Hz, 1H), 7.08 (t,J=7.8 Hz, 1H).

IR (neat) cm⁻¹: 3380 (br), 1743, 1680.

Mass m/z (CI): 399 (M+1).

Example 12 Ethyl3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Step (i):

To a solution of 2-nitro-5-fluorophenol (5 g, 1 eq, 31.6 mmol) and ethyl2-bromoacetate (3.8 ml, 1.1 eq, 34.8 mmol) in dry acetone (160 ml) wasadded anhydrous potassium carbonate (8.7 g, 2 eq, 63.2 mmol) and stirredat RT for 16 h. The reaction mixture was filtered through celite andthen condensed on rotavapour. The residue was diluted with ethyl acetateand washed with water and brine to yield crude compound (6 g, yield78%), which was used in step (ii).

Step (ii):

The crude compound obtained in step (i) (6 g, 1 eq, 28.8 mmol) was takenin dry methanol (150 ml). To this iron powder (8.06 g, 5 eq, 144 mmol)and glacial acetic acid (25 ml, 15 eq, 432 mmol) was added and heated at110° C. for 4 h. The solvents were removed from the reaction mixture anddiluted with ethyl acetate. The ethyl acetate layer was washed withaqueous ammonium chloride, water and brine. The residue waschromatographed to yield3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as solid (2.2 g, mp:204-206° C., yield 46%).

¹H NMR (200 MHz, CDCl₃+DMSO-d₆) δ: 4.52 (s, 2H), 6.60-6.70 (m, 2H), 6.88(dd, J=8.3 and 5.8 Hz, 1H), 10.63 (bs, 1H).

IR (KBr) cm⁻¹: 1677, 1622.

Mass m/z (CI): 168 (M+1).

Step (iii):

3-Oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.2 g, 1 eq, 13.1mmol) obtained in step (ii) in dry THF (10 ml) was added drop wise to arefluxing THF (60 ml) containing LAH (1.5 g, 3 eq, 39.5 mmol). It wasfurther refluxed for 3 h and quenched with ethyl acetate. To this water(1.5 ml), 15% sodium hydroxide (1.5 ml) and water (4.5 ml) were addedsequentially. Once Al(OH)₃.H₂O precipitated out, it was filtered thoughcelite. The filtrate was condensed on rotavapour and chromatographed(ethyl acetate and hexane) to yield7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, yield 65%) asyellow oil.

¹H NMR (200 MHz, CDCl₃) δ: 2.80 (bs, 1H), 3.38 (t, J=4.4 Hz, 2H), 4.24(t, J=4.4 Hz, 2H), 6.48-6.56 (aromatics, 3H).

IR (neat) cm⁻¹: 3395 (br), 2957, 1606.

Mass m/z (CI): 154 (M+1).

Step (iv):

A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq,8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol)in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction mixturewas diluted with ethyl acetate and washed with water and brine. Theresidue was chromatographed using ethyl acetate and hexane to afford3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (1.1g, yield 47%) as viscous oil.

¹H NMR (200 MHz, CDCl₃) δ: 2.10-2.28 (m, 2H), 3.30 (t, J=4.4 Hz, 2H),3.38 (t, J=6.7 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 4.24 (t, J=4.4 Hz, 2H),6.50-6.70 (aromatics, 3H).

Mass m/z (CI): 274 [M(⁷⁹Br)+1], 276 [M(⁸¹Br)+1].

Step (v):

(S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2.20 g, 1 eq, 9.28 mmol)obtained in example 6,3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide (3.30g, 1.3 eq, 12.06 mmol) obtained in step (iv) above, anhydrous K₂CO₃(3.84 g, 3 eq, 27.84 mmol), and tetrabutyl ammonium bromide (597 mg, 0.2eq., 1.85 mmol) were heated at 90° C. in dry toluene (47 mL) for 20 h.The reaction mixture was diluted with ethyl acetate, washed with waterand brine. The residue was chromatographed using ethyl acetate andhexane to afford the title compound (1.78 g, yield 44.5%) as viscousliquid.

[α]_(D): −9.2° (c 1.0, MeOH).

¹H NMR (200 MHz, CDCl₃) δ: 1.17 (t, J=7 Hz, 3H), 1.23 (t, J=7 Hz, 3H),1.89 (q, J=6.8 Hz, 2H), 2.90 (d, J=6.5 Hz, 2H), 3.10-3.42 (m, 7H),3.45-3.65 (m, 1H), 3.95 (t, J=6.7 Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70(m, aromatics, 5H), 7.05 (d, J=8.4 Hz, 2H).

IR (neat) cm⁻¹: 3394 (br), 2978, 1740, 1617, 1514.

Mass m/z (CI): 431 (M+1).

1. Novel compounds of formula (I)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their salts, their solvates wherein W represents NR¹², R¹² represents hydrogen, R¹⁰ and R¹¹ may be same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R⁵ represents to hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶ forms a bond together with R⁵; R⁷ may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R⁸ may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR¹³, where R¹³ represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; R⁸ and R¹³ together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m is an integer 0-6.
 2. A compound according to claim 1, which is selected from: (±) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (+) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (−) Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (±) Ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate (+) Ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate (−) Ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2′-bromoethyl)}aminophenyl]propanoate (±) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate (+) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate (−) Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate (±) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (+) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (−) Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (±) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (+) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (−) Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (±) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate (+) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate (−) Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate.
 3. Process for the preparation of compound of formula (I)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their salts, their solvates wherein W represents NR¹², R¹² represents hydrogen, R¹⁰ and R¹¹ may be same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R⁵ represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R⁶; R⁶ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R⁶ forms a bond together with R⁵; R⁷ may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R⁸ may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR¹³, where R¹³ represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; R⁸ and R¹³ together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m is an integer 0-6 which comprises: a. i. Reacting compound of formula (IIIh) O₂N—Ar—CHO  (IIIh) where Ar is as defined above with compound of formula (IIIi)

where R¹³ represents (C₁-C₆)alkyl group and all other symbols are as defined earlier in the presence of a base selected from metal hydride like NaH or KH; organolithiums like CH₃Li or BuLi; alkoxides like NaOMe, NaOEt or t-BuO⁻K⁺ or a mixture thereof and a solvent selected from diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide or a mixture thereof. The reaction can be carried out in the presence or absence of HMPA as a cosolvent at a temperature in the range from −78° C. to 50° C., preferably at a temperature in the range of −10° C. to 30° C. under anhydrous conditions to obtain a compound of formula (IIIg)

where R⁷, R⁸ and Ar are as defined above. ii. Reduction of the compound of formula (IIIg) to a compound of formula (I) where m is 0 and all other symbols are as defined above in the presence of gaseous hydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof preferably 5-10 Pd/C and a solvent selected from such as dioxane, acetic acid, ethyl acetate or a mixture thereof. The reaction is carried out at a pressure between atmospheric pressure and 80 psi. The amount of catalyst used is in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. The reduction can be carried out in the presence of metal catalysts selected from Rhodium, Ruthenium or Indium containing chiral ligands selected from (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane or (−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane to obtain a compound of formula (IIIb) in optically active form. or b. i. Diazotization of the compound of formula (IIIk)

where m is 0 and all other symbols are as defined above, to a compound of formula (IIIl)

where m is 0 and all other symbols are as defined above in the presence of diazotizing agent selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite under acidic conditions using acids selected from sulfuric acid, HCl or acetic acid, in an organic solvent selected from alcohol like methanol, ethanol or propanol; 1,4-dioxane, THF or acetone and the like. Etherifying the residue using alkylating agent selected from alkyl sulfate like diethyl sulphate or dimethylsulphate; alkyl halide like ethyl iodide or methyliodide, in solvent selected from hydrocarbons like toluene or benzene; DMF, DMSO, acetonitrile, THF or methyl isobutyl ketone (MIBK), in an alkali base selected from sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride or potassium hybrid. ii. Reduction of compound of formula (IIIl) to a compound of formula (I) where m is 0 and all other symbols are as defined above in the presence of gaseous hydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof preferably 5-10% Pd/C and a solvent selected from such as dioxane, acetic acid, ethyl acetate or a mixture thereof. The reaction is carried out at a pressure between atmospheric pressure and 80 psi. The amount of catalyst used is in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. The reduction can be carried out in the presence of metal catalysts selected from Rhodium, Ruthenium or Indium containing chiral ligands selected from (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane or (−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane to obtain a compound of formula (I) in optically active form. or c. i. Reaction of compound of formula (IIIi)

where all symbols are as defined above with a compound of formula (IVa)

where m is 1-6 and all other symbols are as defined above to yield a compound of formula (IVb)

where m is 1-6 and all other symbols are as defined above in the presence of a base selected from metal hydride like NaH or KH; organolithiums like CH₃Li or BuLi; alkoxides like NaOMe, NaOEt or t-BuO⁻K⁺ or a mixture thereof and a solvent selected from diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide or a mixture thereof. The reaction can be carried out in the presence or absence of HMPA as a cosolvent at a temperature in the range from −78° C. to 50° C., preferably at a temperature in the range of −10° C. to 30° C. ii. Reduction of the compound of formula (IVb) to yield a compound of formula (IVc)

where m is 1-6 and all other symbols are as defined above in the presence of gaseous hydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof preferably 5-10% Pd/C and a solvent selected from such as dioxane, acetic acid, ethyl acetate or a mixture thereof. The reaction is carried out at a pressure between atmospheric pressure and 80 psi. The amount of catalyst used is in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. The reduction can be carried out in the presence of metal catalysts selected from Rhodium, Ruthenium or Indium containing chiral ligands selected from (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane or (−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane to obtain a compound of formula (IVc) in optically active form. iii. Reaction of the compound of formula (IVc) with a compound of formula (IVd) R¹²—NH₂  (IVd) where R¹² is defined above in a solvent selected from CH₂Cl₂, CHCl₃, chlorobenzene, benzene or THF, in the presence of catalyst selected from p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH or BF₃—OEt₂ or activated molecular sieves at a temperature in the range of 10° C. to 100° C., preferably at a temperature in the range from 10° C. to 60° C. The imine product initially produced is reduced using Na(CN)BH₃—HCl, H₂—Pd/C, H₂—Pt/C or H₂-Ph/C in a solvent selected from methanol or ethanol to yield a compound of formula (I) where m is 1-6 and all other symbols are defined above. or d. i. Diazotization of the compound of formula (IIIk) where m is 0, R⁶ is hydrogen and all other symbols are as defined above to obtain a compound of formula (Va)

where m is 0, R⁶ is hydrogen and all other symbols are as defined above in the presence of diazotizing agent selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite, catalytic amount of carboxylic acid selected from acetic acid or propionic acid, in a solvent selected from chloroform, chlorobenzene, dichloroethane or a mixture thereof at a temperature in the range of room temperature and reflux temperature of the solvent employed for a period in the range of 0.5 to 16 h. ii. Decomposing the arylalkyl diazo acetate of the formula (Va) to obtain a compound of formula (IIIl) where m is 0, R⁶ is hydrogen, R⁷ is as defined earlier excluding hydrogen and all other symbols are as defined earlier in the presence of a catalyst selected from Rh(II)acetate, salt/complex of Cu(I) or Rh(II) in the presence of an alcohol of the formula R⁷OH where R⁷ is as defined above. iii. Reduction of the compound of formula (IIIl) to yield a compound of formula (I) where m is 0, R⁶ is hydrogen, R⁷ is as defined earlier excluding hydrogen and all other symbols are as defined earlier is carried out in the presence of gaseous hydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof, a solvent selected from dioxane, acetic acid or ethyl acetate at a pressure between atmospheric pressure and 80 psi. The catalyst used is preferably 5-10% Pd/C and the amount of catalyst used is in the range of 1-50% w/w. The hydrogenation can also be carried out using ammonium formate, cyclohex-1,4-diene type of hydrogen donor under pd/c conditions using a solvent selected from methanol, ethanol or ethyl acetate. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. or e. i. Diazotization of the compound of formula (VIa)

where m is 0, R⁵=R⁶=R⁸=H and all other symbols are as defined above to a compound of formula (VIb)

where m is 0, R⁵=R⁶=R⁸=H, Y is oxygen and all other symbols are as defined above is carried out in the presence of diazotizing agent selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite under aqueous acidic conditions using acids selected from sulfuric acid, HCl or acetic acid, in an organic solvent selected from alcohols like methanol, ethanol or propanol; 1,4-dioxane, TIE or acetone. ii. One pot esterification and etherification of compound of formula (VIb) to a compound of formula (VIc)

where m is 0, R⁵=R⁶=H, Y is oxygen and all other symbols are as defined above is carried by initial di deprotonation of (VIb) using a base selected from NaH, KH or KOH, in presence of a solvent selected from toluene, benzene, diethylether, THF, DMF, DME or HMPA, followed by treatment with an alkylating agent selected from alkyl halide like ethyl iodide or methyl iodide; Et₃O⁺BF₄ ⁻, Me₃O⁺BF₄ ⁻, dialkylsulfate like dimethyl sulfate or diethyl sulfate at a temperature in the range of 0° C. to 100° C. iii. Nitration of the compound of formula (VIc) to a compound of formula (VId)

where m is 0, R⁵=R⁶=H, Y is oxygen and all other symbols are as defined above is carried out using a nitrating agent selected from fuming nitric acid, N₂O₅, a mixture of conc. Nitric acid and conc. Sulfuric acid or a mixture of nitric acid and acetic anhydride in the presence of a solvent or under neat condition at a temperature in the range of −10° C. to room temperature for a period in the range of 0.5 to 4 h. iv. Reduction of the compound of formula (VW) to a compound of formula (I) in its enantiomerically pure form where m is 0, R⁵=R⁶=H, Y is oxygen and all other symbols are as defined above is carried out in the presence of gaseous hydrogen and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof preferably 5-10% Pd/C and a solvent selected from such as dioxane, acetic acid, ethyl acetate or a mixture thereof. The reaction is carried out at a pressure between atmospheric pressure and 80 psi. The amount of catalyst used is in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. or f. i. Diazotization of the compound of formula (VIIa)

where m is 0, R¹=R²=H and all other symbols are as defined earlier to a compound of formula (VII b)

where m is 0, R¹=R²=H and all other symbols are as defined earlier is carried out in the presence of a diazotizing agent selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite under aqueous acidic conditions using an acid selected from sulfuric acid, hydrochloric acid or acetic acid, in presence of an optional co solvent like an alcohol selected from methanol, ethanol or propanol; ether selected from 1,4-dioxane or THF; ketones selected from acetone or methyl ethyl ketone. iii. Esterification of the compound of the formula (VII b) to a compound of formula (VII c)

where m is 0, R¹=R²=H and all other symbols are as defined earlier is carried out in the presence of an alcohol R⁸—OH where R⁸ represents lower alkyl groups like methyl; ethyl, propyl, isopropyl, n-butyl or t-butyl and a catalyst like conc. sulfuric acid, dry HCl or BF₃—OEt₂ at reflux temperature of the alcohol employed. Alternatively reagents like diazomethane, Et₃O⁺BF₄ ⁻ or Me₃O⁺BF₄ ⁻ can be used for esterification. iv. Selective O-alkylation of the compound of formula (VIIc) to the compound of formula (VIId)

where m is 0, R¹=R²=H, Y is oxygen and all other symbols are as defined earlier is carried out in the presence of an alkylating agents selected from an alkyl sulfate like diethyl sulfate or dimethyl sulfate; alkyl halides like ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide or isopropyl iodide, in a solvent selected from a hydrocarbon like toluene or benzene; acetonitrile, tetrahydro furan, dimethyl formamide or dimethyl sulfoxide, in the presence of molecular sieves and an alkali base selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium hydride, sodium or potassium hydroxide. Heavy metal oxides selected from Ag₂O, PbO or HgO are of particular use to carry out alkylation when alkyl halides are used as alkylation reagent. Phase transfer catalysts selected from tetraalkylammonium hydroxide or tetraalkylammonium halides such as tetrabutylammonium chloride or tetrabutylammonium bromide can also be employed. v. Reduction of compound of the formula (VIId) to a compound of formula (I) where m is 0, R¹=R²=H, Y is oxygen and all other symbols are as defined earlier, is carried out in the presence of gaseous hydrogen or hydrogen donors selected from ammonium formate or cyclohex-1,4-diene and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof in a solvent selected from methanol, ethanol, dioxane, acetic acid or ethyl acetate at a pressure between atmospheric pressure and 80 psi. The catalyst used is preferably 5-10% Pd/C and the amount of catalyst used in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. or g. i. Diazotization of the compound of formula (VIIa)

where m is 0, R¹=R²=H and all other symbols are as defined earlier to a compound of formula (VII b)

where m is 0, R¹=R²=H and all other symbols are as defined earlier is carried out in the presence of a diazotizing agent selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite under aqueous acidic conditions using an acid selected from sulfuric acid, hydrochloric acid or acetic acid, in presence of an optional co solvent like an alcohol selected from methanol, ethanol or propanol; ether selected from 1,4-dioxane or THF; ketones selected from acetone or methyl ethyl ketone. iii. Esterification of the compound of the formula (VII b) to a compound of formula (VII c)

where m is 0, R¹=R²=H and all other symbols are as defined earlier is carried out in the presence of an alcohol R⁸—OH where R⁸ represents lower alkyl groups like methyl, ethyl, propyl, isopropyl, n-butyl or t-butyl and a catalyst like conc. sulfuric acid, dry HCl or BF₃—OEt₂ at reflux temperature of the alcohol employed. Alternatively reagents like diazomethane, Et₃O⁺BF₄ ⁻ or Me₃O⁺BF₄ ⁻ can be used for esterification. iv. Reduction of compound of the formula (VIIc) to a compound of formula (VIIIa)

where m is 0, R¹=R²=H and all other symbols are as defined earlier, is carried out in the presence of gaseous hydrogen or hydrogen donors selected from ammonium formate or cyclohex-1,4-diene and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof in a solvent selected from methanol, ethanol, dioxane, acetic acid or ethyl acetate at a pressure between atmospheric pressure and 80 psi. The catalyst used is preferably 5-10% Pd/C and the amount of catalyst used in the range of 1-50% w/w. Alternatively, the reduction can also be carried out by employing metal solvent reduction like magnesium, iron, tin, samarium or sodium amalgam in alcohol like methanol, ethanol or propanol preferably methanol. v. N,N-dibenzylation of the compound of formula (VIIIa) to the compound of formula (VIIIb)

where m is 0, R¹=R²=H and all other symbols are as defined earlier, is carried out by treating with an alkylating agent selected from benzyl halides like benzyl bromide or benzyl chloride in a solvent selected from a hydrocarbon like toluene or benzene or acetonitrile, tetrahydro furan, dimethyl formamide, dimethyl sulfoxide, in the presence of an alkali base selected from sodium carbonate, potassium carbonate, sodium or potassium hydroxide in the absence or presence of a phase transfer catalyst selected from tetraalkylammonium hydroxide or a tetraalkylammonium halide like tetrabutylammonium chloride or tetrabutylammonium bromide at a temperature in the range of room temperature to the reflux temperature of the solvent employed. vi. Hydrolysis of the compound of the formula (VIIIb) to the compound of formula (VIIIc)

where m is 0, R¹=R²=H and all other symbols are as defined earlier, is carried out using an aqueous alkali metal base selected from lithium carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide, in a suitable co-solvent selected from methanol, ethanol, THF or a mixture thereof at a temperature in the range of 0° C. to 80° C. for a period in the range of 0.5 h to 24 h, preferably 0.5 h to 3-4 h. vii. One pot esterification and etherification of the compound of the formula (VIIIc) to the compound of formula (VIIId)

where m is 0, R¹=R²=H, R⁵=R⁶ and is as defined above and all other symbols are as defined earlier, is carried out by treating with a base selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, in a solvent selected from a hydrocarbon like toluene or benzene; dialkyl ethers like diethyl ether or tetrahydro furan; dimethyl formamide or HMPA followed by treatment with an alkyl halide selected from ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide or isopropyl iodide; an alkyl sulfate like diethyl sulfate or dimethyl sulfate; Et₃O⁺BF₄ ⁻ or Me₃O⁺BF₄ ⁻ at a temperature in the range of 0° C. to 80° C. for a period in the range of 2 h to 20 h. viii. Debenzylation of the compound of the formula (Wild) to the compound of formula (I) where m is 0, R¹=R²=H, R⁵=R⁶ and is as defined above and all other symbols are as defined earlier, is carried out in the presence of gaseous hydrogen or hydrogen donors selected from ammonium formate or cyclohex-1,4-diene and a catalyst selected from Pd/C, Rh/C, Pt/C, Raney nickel or a mixture thereof in the presence of a solvent selected from methanol, ethanol, dioxane, acetic acid or ethyl acetate. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst used is preferably 5-10% Pd/C and the amount of catalyst used in the range of 1-50% w/w. 